Angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. Although stimulators of angiogenesis are receiving growing attention for the treatment of cardiovascular diseases, inhibitors of angiogenesis have been the focus of research activity due to their ability to slow tumor progression. While angiogenesis is crucial for the progression of tumors the more recent concept of lymphangiogenesis is suspected as being of greater importance in relation to metastatic spread and indeed clinicopathological data suggest that the lymphatics are an initial route for the spread of solid tumors. Recently, members of the VEGF family of growth factors have been implicated as key mediators of lymphangiogenesis in both normal biology and tumors.

Although there are multiple opportunities for the development of anti-angiogenic molecules, the most advanced targets are the growth factors. The principal growth factors driving angiogenesis are VEGF, bFGF, and hepatocyte growth factor/scatter factor. Discovered in the 1980's, VEGF is one of the archetypal angiogenic growth factors and has received considerable attention. VEGF is a homodimeric 45kDa glycoprotein that specifically acts on endothelial cells binding to a growing number of endothelial tyrosine kinase receptors including Flt-1 (VEGFR-1) and KDR/flk-1 (VEGFR-2). The related VEGFC binds to VEGFR-3/Flt-4. VEGFR-2 is exclusively expressed in endothelial cells and appears to play a pivotal role in endothelial cell differentiation and vasculogenesis. VEGFR-3 has been implicated in lymphogenesis.

Novartis researchers have recently reported the discovery of a series of anthranilamide that can inhibit VEGF receptor tyrosine kinase. Candidates from this series potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. These molecules potently inhibit VEGF-induced angiogenesis in an implant model, with ED50 values of 7 mg/kg. In a mouse orthotopic model melanoma growth and metastases was reduced.

Approximately 555,500 people die from cancer in the United States each year. The development of therapeutic strategies for the prevention and treatment of cancer thus represents a key priority for the pharmaceutical industry (see "Cancer Treatment 2002" for a full analysis of current and future pharmaceutical approaches to cancer). It is hoped that molecules such as Novartis’ anthranilamide will lead to the development of improve anticancer drugs thereby reducing cancer mortality.

Entry date February, 2003

Adapted from Manley et al, J Med Chem 2002 Dec 19;45(26):5687-93.

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